HSP90 is a major intracellular chaperone protein. Chaperone proteins are proteins that bind to various proteins to assist in folding of the bound proteins. A group of proteins whose folding requires HSP90 are generally called HSP90 client proteins.
It is assumed that HSP90 as well as multiple proteins such as co-chaperones, partner proteins and immunophilins are involved in the mechanism of folding of client proteins by HSP90 and that they collaboratively assist in folding of HSP90 client proteins (Non Patent Document 1); however, the details of the mechanism are still not sufficiently clear.
It is assumed that HSP90 client proteins form a complex with HSP90, co-chaperones and the like and are then conformationally changed to mature proteins and that the proteins are ubiquitinated and degraded by proteasomes when they are not folded normally by HSP90 and the like (Non Patent Documents 1 to 4).
In recent years, HSP90 inhibitors have been expected as candidates for therapeutic agents for various diseases (for example, cancer, neurodegenerative diseases such as Alzheimer's disease, cardiovascular diseases, infections, autoimmune diseases, and diseases associated with apoptotic cell injury) (Non Patent Document 2).
In particular, since many cancer-associated proteins including molecular targets for anticancer agents are HSP90 client proteins, HSP90 inhibitors have been expected as candidates for anticancer agents. For example, multiple proteins involved in the occurrence and development of cancer such as Her2, Raf, Akt and telomerase are known as HSP90 client proteins (Non Patent Document 1). It is assumed that these cancer-associated proteins are changed from immature proteins to mature proteins and act to cause malignant transformation of cells, respectively, by use of HSP90 as a chaperone protein. HSP90 is a protein that exists not only in cancer cells but also in normal cells, and it is reported that the affinity with a client protein and the ATPase activity necessary for its chaperone activity are higher in cancer cells than in normal cells (Non Patent Documents 1 to 3). Therefore, HSP90 inhibitors are assumed to be capable of inactivating multiple cancer-associated proteins simultaneously in a cancer cell-specific manner, and have been expected as candidates for anticancer agents that are potent and have a broad antitumor spectrum.
Geldanamycin, herbimycin, 17-allylaminogeldanamycin (17-AAG) and the like are conventionally known as HSP90 inhibitors (Non Patent Documents 1 to 4). These compounds bind to the ATP binding pocket at the N-terminal of HSP90 and inhibit binding of HSP90 to ATP in order to inhibit the function of HSP90 as a chaperone protein. Various compounds inhibiting HSP90 are reported in addition to the above compounds (Patent Document 1, Patent Document 2, Patent Document 3, Non Patent Document 5 and Non Patent Document 6) and a tricyclic pyrazolopyrimidine derivative is also reported (Patent Document 4).
Moreover, several publications have reported the intended uses of tricyclic pyrazolopyrimidine derivatives and compounds having a condensed ring structure, which also have three constituent heterocyclic rings, for anticancer purposes (Patent Documents 5 to 9, and Non Patent Documents 7 and 8).